Tuning the β-turn segment in designed peptide β-hairpins: Construction of a stable type I′ β-turn nucleus and hairpin–helix transition promoting segments



Designed octapeptides Boc-Leu-Val-Val-Aib-DXxx-Leu-Val-Val-OMe (DXxx = DAla, 3a;DVal, 3c and DPro, 5a) and Boc-Leu-Phe-Val-Aib-DAla-Leu-Phe-Val-OMe (3b) have been investigated to construct models of a stable type I′ β-turn nucleated hairpin and to generate systems for investigating helix–hairpin conformational transitions. Peptide 5a, which contains a central Aib-DPro segment, is shown to adopt a stable type I′ β-turn nucleated hairpin structure, stabilized by four cross-strand hydrogen bonds. The stability of the structure in diverse solvents is established by the observation of all diagnostic NOEs expected in a β-hairpin conformation. Replacement of DPro5 by DAla/DVal (3a–c) results in sequences that form β-hairpins in hydrogen bonding solvents like CD3OH and DMSO-d6. However, in CDCl3 evidence for population of helical conformations is obtained. Peptide 6b (Boc-Leu-Phe-Val-Aib-Aib-Leu-Phe-Val-OMe), which contains a centrally positioned Aib-Aib segment, provides a clear example of a system, which exhibits a helical conformation in CDCl3 and a significant population of both helices and hairpins in CD3OH and DMSO-d6. The coexistence of multiple conformations is established by the simultaneous observation of diagnostic NOEs. Control over stereochemistry of the central β-turn permits generation of models for robust β-hairpins and also for the construction of systems that may be used to probe helix–hairpin conformational transitions. © 2006 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 88: 350–361, 2007.

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